Cytokinesis is the process where the cytoplasm is divided, partitioning a copy of the duplicated genome to each daughter cell. It is important that this process by temporarily regulated such that it occurs only after chromosomes have been segregated at the end of mitosis. The fission yeast, S. pombe, is ideally suited for the study of cytokinesis since, like animal cells, they divide by medial fission using an F-actin contractile ring. Sid1p and Sid2p are highly conserve protein kinases identified in a screen for S. pombe mutations in genes that regulate cytokinesis. In sid1 and sid2 mutants, the machinery needed for cytokinesis, the actin contractile ring, is assembled but cells arrest prior to contraction. In a striking pattern consistent with this phenotype, Sid2p is localized transiently to unique sites flanking either side of the cleavage furrow and to spindle pole bodies throughout the cell cycle. These and other results, suggest that the sid kinases participate in a novel signaling pathway that regulates the completion of cytokinesis. In this study, we propose to use a combination of genetic and biochemical approaches to elucidate the mechanisms that regulate these kinases through the cell cycle and to map out this novel signaling pathway. These studies will allow us to define the regulatory cascade for cytokinesis in S. pombe. Based on Sidp homology to mammalian proteins, these studies should yield insight into the basic question of how cytokinesis is coordinated with mitosis in all eukaryotic cells and how when compromised, it could lead to genomic instability and cancer.